PTX3, a humoral pattern recognition molecule at the interface between microbe and matrix recognition

Available online at www.sciencedirect.com

ScienceDirect PTX3, a humoral pattern recognition molecule at the interface between microbe and matrix recognition Cecilia Garlanda1, Sebastien Jaillon1, Andrea Doni1, Barbara Bottazzi1 and Alberto Mantovani1,2 Innate immunity consists of a cellular and a humoral arm. PTX3 is a fluid patter recognition molecule (PRM) with antibody-like properties. Gene targeted mice and genetic associations in humans suggest that PTX3 plays a non-redundant role in resistance against selected pathogens (e.g. Aspergillus fumigatus, Pseudomonas aeruginosa, uropathogenic Escherichia coli) and in the regulation of inflammation. PTX3 acts as an extrinsic oncosuppressor by taming complement elicited tumor-promoting inflammation. Recent results indicate that, by interacting with provisional matrix components, PTX3 contributes to the orchestration of tissue repair. An acidic pH sets PTX3 in a tissue repair mode, while retaining anti-microbial recognition. Based on these data and scattered information on humoral PRM and matrix components, we surmise that matrix and microbial recognition are related functions in evolution. Addresses 1 Humanitas Clinical Research Center, via Manzoni 56, 20089, Rozzano (Milano), Italy 2 Humanitas University, via Manzoni 56, 20089 Rozzano, Italy Corresponding author: Mantovani, Alberto ([email protected])

Current Opinion in Immunology 2016, 38:39–44 This review comes from a themed issue on Innate immunity Edited by Eric Vivier and Ruslan Medzhitov

http://dx.doi.org/10.1016/j.coi.2015.11.002 0952-7915/# 2015 Elsevier Ltd. All rights reserved.

Introduction Pentraxins are a superfamily of evolutionarily conserved proteins with multi-functional properties in innate immunity (i.e. regulation of complement activation and opsonisation of pathogens). They are characterized by a cyclic multimeric structure and a pentraxin domain (200 amino acid) in their carboxy-terminal region containing a pentraxin signature (HxCxS/TWxS, where x is any amino acid) [1,2]. Based on the primary structure of the protomer, pentraxins were divided into short and long pentraxins. C-reactive protein (CRP) and serum amyloid P (SAP) are www.sciencedirect.com

prototypic short pentraxins produced by hepatocytes and constitute the main acute phase proteins in human and mouse, respectively, while PTX3 is the first long pentraxin identified in the early 1990s. PTX3, the main focus of this review, was identified as an IL-1 or TNF-inducible gene. Data collected over the years demonstrate that PTX3 acts as a fluid phase pattern recognition molecule (PRM) and regulator of inflammation [3,4,5,6,7,8]. In particular PTX3 exerts nonredundant functions in resistance against selected pathogens, a finding at the basis of ongoing translational efforts. Here we review recent progress made in defining the structure, immunobiology and in vivo role of PTX3, which we used as a paradigm for humoral innate immunity. Based on recent and scattered results [8], we propose that matrix and microbe recognition are evolutionary linked processes.

The long pentraxin PTX3 PTX3 is a 381 aa long secreted molecule characterized by a C-terminal pentraxin like domain and a unique Nterminal domain unrelated to any known protein. Both human and murine PTX3 genes are localized on the chromosome 3 and organized in three exons. The leader peptide and the N-terminal domain of PTX3 are coded by the first two exons, respectively, and the C-terminal pentraxin domain is coded by the third exon. The promoter of both human and murine PTX3 gene displays potential binding sites for many transcription factors including Pu1, AP-1, HIF-1a, C/EBPbeta, NF-kB, Sp1 and NF-IL-6. The IL-1RI/MyD88 pathway is involved in the induced of PTX3 in different sterile models of tissue injury [7,8,9], whereas the TLR4/MyD88 pathway controls PTX3 production in infectious conditions, for instance in urinary tract infections mediated by uropathogenic Escherichia coli [6]. The primary sequence of PTX3 is highly conserved, suggesting an evolutionary pressure to maintain a functional role [1]. PTX3 has a unique quaternary structure with eight subunits associated to form an octamer by covalent interactions between cysteine residues present on both the N-terminal and C-terminal domain [10]. A single N-glycosylation site at Asn220 is occupied by complex type oligosaccharides [11]. PTX3 interacts with different ligands including microbial moieties, complement components and extracellular matrix components. Current Opinion in Immunology 2016, 38:39–44

40 Innate immunity

The glycosidic moiety is involved in the interaction between PTX3 and selected ligands, such as P-selectin and influenza virus [12,13]. The N-terminal domain is responsible for the interaction with different PTX3 ligands, including microbial components, FGF2, Factor H, but the full-length molecule is required for optimal binding of most ligands. Recently, it has been shown that PTX3 interacts with fibrinogen and plasminogen in acidic conditions, through the N-terminal domain [8]. PTX3 is expressed by various myeloid cell types (dendritic cells, monocytes, macrophages, neutrophils), epithelial cells, vascular and lymphatic endothelial cells, and mesenchymal cells (e.g. fibroblasts and adipocytes), upon exposure to inflammatory signals (e.g. TNFa, IL1b), TLR agonists, and microbial moieties (e.g. LPS, OmpA) [2]. PTX3 expressed by mammary epithelial cells and by uroepithelial cells contributes to innate resistance to infections in neonates and urinary tract infections, respectively [6,14], whereas PTX3 produced by mesenchymal cells contributes to tissue repair processes [8]. As opposed to de novo synthetized PTX3, neutrophils store this PRM in their granules and rapidly release the protein, in part associated with neutrophil extracellular traps (NETs), in response to microorganisms or TLR agonists, thus contributing to resistance to infections [5].

Role of PTX3 in innate resistance to infections Since its identification, PTX3 has emerged as a fluid phase PRM exerting a protective role in resistance against selected fungal, bacterial and viral pathogens, including Aspergillus fumigatus, Paracoccidoides brasiliensis, Pseudomonas aeruginosa, Klebsiella pneumoniae, influenza virus, by acting as an opsonin for bacteria and fungi, facilitating recognition and phagocytosis in an Fcg receptor- and complement-dependent manner, and by neutralizing virus infectivity [2]. More recently, the protective role of PTX3 has been extended to urinary tract infections, where PTX3 emerged as an essential component of innate resistance against uropathogenic Escherichia coli, acting by facilitating neutrophil-dependent microbial clearance [6]. PTX3 was also found to interact with acapsular Neisseria meningitidis, through outer membrane vesicles and selected meningococcal antigens and to reduce the bacterial load in infected infant rats, acting as an amplifier of responses to this bacterium [15]. In contrast with the described protective role of PTX3 in viral infections, it has recently been shown that PTX3 interacts through the N-terminal domain to arthritogenic alphaviruses (chikungunya virus and Ross River virus), facilitating viral entry and replication during the acute phase of infection, and causing enhanced viral infectivity and prolonged disease [16,17]. Current Opinion in Immunology 2016, 38:39–44

Several studies have reported single nucleotide polymorphisms (SNPs) in the PTX3 gene. Most SNPs are located in non-coding regions, and one exonic SNP causes an amino acid variation of the protein. When associated in particular haplotypes, three PTX3 SNPs influence susceptibility to infections. In particular, PTX3 variants are associated with susceptibility to pulmonary tuberculosis [18], Pseudomonas aeruginosa infections in cystic fibrosis Caucasian patients [19], Aspergillus fumigatus infections in patients undergoing hematopoietic stem cell transplantation [20], fungal infections in solid organ transplanted patients [21], and urinary tract infections [6]. Specific PTX3 haplotypes have been associated to higher protein expression [20,22], but the molecular mechanisms responsible of this association are still poorly understood. These data underline the functional evolutionary conservation of PTX3 in innate responses to microbes.

Regulation of inflammation and resistance to microbes by PTX3: activation and regulation of complement Several evidences indicate that PTX3 plays a role in inflammation: i) production by myeloid and stromal cells in inflammatory conditions [23]; ii) amplification of the pro-inflammatory effects of recognized microbial moieties [4,24]; iii) higher tissue damage in ptx3-deficient mice [6,9] and lower susceptibility to endotoxic shock in PTX3 over-expressing animals [25]. In particular genetic models have been essential to define that PTX3 can exert a regulatory role on inflammation through modulation of complement activation and regulation of inflammatory cell recruitment. PTX3 modulates all the three complement pathways, (e.g. the classical, the alternative and the lectin pathways) through the interaction with different complement components, including negative regulators [26,27,28,29,30, 31,32,33]. PTX3 interaction with surface immobilized C1q activates the classical complement cascade promoting C3 and C4 deposition, while interaction in the fluid phase inhibits the complement cascade via competitive blocking of relevant interaction sites. PTX3 interacts with members of the lectin pathway, i.e. ficolin-1, ficolin-2 and mannose binding lectin (MBL), and enhances ficolin-2and MBL-dependent complement deposition on the surface of Aspergillus fumigatus and Candida albicans, respectively [29,30,31,34]. Formation of the MBL/PTX3 complex recruits C1q, promotes C4 and C3 deposition on Candida albicans and enhances the phagocytosis of the pathogen. Similarly, immobilized PTX3 is able to trigger ficolin-1-dependent activation of the lectin complement pathway [34]. In addition, surface-bound PTX3 enhances Factor H (FH) recruitment and iC3b deposition, modulating the activation of the alternative complement pathway and preventing an excessive inflammatory response to tissue www.sciencedirect.com

PTX3 in innate immunity and inflammation Garlanda et al. 41

injury, while increasing the deposition of opsonic molecules [28]. Similarly, PTX3 recruits C4 binding protein (C4BP) on apoptotic cells reducing the deposition of the lytic C5b-9 terminal complex [32]. Also in this case PTX3 is capable of targeting functionally active C4BP to sites of tissue injury, thus limiting complement-mediated inflammation. Mutation and polymorphisms of FH leading to dysregulation of the alternative complement pathway are associated with various diseases, including atypical hemolytic uremic syndrome (aHUS). Interestingly, mutations in FH observed in patients with aHUS are associated with a reduced interaction between FH and PTX3 [35]. Given the capability of PTX3 to recruit FH and to control excessive local complement activation, the defective interaction between the two molecules in aHUS patients could amplify local complement-mediated inflammation essential in the pathogenesis of the disease. The modulation of complement activity by PTX3 is involved in the regulation of tissue damage observed in a murine model of acute myocardial infarction [9], as well as in cancer models (see below). Besides complement activation, PTX3 can regulate the inflammatory response acting on cell recruitment. PTX3 binds the adhesion molecule P-selectin, an interaction occurring via its N-linked glycosidic moiety [12], and inhibits leukocyte rolling on endothelium. In agreement, PTX3 administration in vivo reduces leukocytes recruitment in models of pleurisy, acute lung injury and ischemia/reperfusion-induced kidney damage [12,36].

increased susceptibility to 3-MCA-induced carcinogenesis and macrophage recruitment. In addition, CCL2-inibition was sufficient to revert the increased susceptibility of PTX3-deficient mice to 3-MCA and the M2-like phenotype of tumor-associated macrophages. These results indicate that in 3-MCA-induced sarcoma, unleashed Complement activation and increased C5a production associated to PTX3-deficiency are likely responsible of exacerbated production of chemokines, which in turn cause increased recruitment of tumor promoting macrophages and favor M2-like polarization [37]. These data are in line with studies showing that C5a plays a pro-tumoral role by recruiting myeloid-derived suppressor cells, amplifying their T cell suppression activity and CCL-2 production [39], and represents a potent inducer of IL1b and IL-17 response in neutrophils thus promoting colon carcinogenesis [40]. Studies in human esophageal squamous cell carcinoma had shown that the PTX3 promoter is hypermethylated in this cancer and PTX3 expression is inhibited [41]. Along the same line, epigenetic analysis showed that PTX3 promoter and regulatory regions were highly methylated in selected human mesenchymal and epithelial tumors [7]. This epigenetic modification was responsible of silencing of PTX3 protein expression since treatment of cancer cells with a methylation inhibitor (5-Aza-20 deoxycytidine) rescued PTX3 protein expression. Thus, PTX3 acts as an extrinsic oncosuppressor gene in mouse and man by acting at the level of Complement-mediated, macrophage-sustained, tumor promoting inflammation.

Role of PTX3 in cancer Inflammation is an essential component of the tumor microenvironment that sustains tumor development and growth [37]. The role of PTX3 as paradigm of humoral innate immunity in cancer-related inflammation has been recently investigated [7]. Results showed that PTX3deficiency in mice caused increased susceptibility to mesenchymal and epithelial carcinogenesis in the models of 3-Methylcholanthrene (3-MCA)-induced carcinogenesis, and 7,12-dimethylbenz [a] anthracene/terephthalic acid (DMBA/TPA)-induced skin carcinogenesis. In these models, PTX3 was produced by infiltrating macrophages and endothelial cells in response to IL-1. PTX3-deficiency was associated with exacerbated cancer-related inflammation as revealed by enhanced macrophage tumor infiltration, pro-inflammatory cytokine production, angiogenesis, and complement C3 deposition and C5a levels. In addition, increased DNA damage was observed in PTX3deficient tumors, as demonstrated by increased Trp53 mutations, oxidative DNA damage and expression of DNA damage (DDR) markers, in line with the evidence that cancer-related inflammation (CRI) is potentially a cause of gene instability [38]. In the 3-MCA-induced cancer model, PTX3 regulated C3-deposition on sarcoma cells by interacting with and recruiting the negative regulator FH. Indeed, genetic inactivation of C3 reverted the www.sciencedirect.com

PTX3 binds through the N-terminal domain selected fibroblast growth factors (FGFs), including FGF2, and FGF8b, and inhibits FGF-dependent angiogenic responses [42]. PTX3-overexpression in cancer cells is associated with reduced angiogenesis and tumorigenic potential in FGFdependent murine tumors, including prostate cancer [43], and transgenic mice overexpressing PTX3 in endothelial cells are protected in different FGF-dependent cancer models [44]. The actual significance of this pathway in primary carcinogenesis remains to be established. In contrast to the evidences outlined above, there are two reports suggesting that PTX3 may play a pro-tumorigenic role, but through poorly defined mechanisms [45,46].

Role of PTX3 in tissue repair The cellular arm of innate immunity contributes to tissue repair by sensing damage-associated molecular patterns, such as matrix components, nuclear proteins and nucleic acids, and initiating tissue repair processes. Recently, PTX3 has been shown to play a non-redundant role in tissue repair in different models of tissue damage (skin wound healing, chemically-induced sterile liver and lung injury, arterial thrombosis) [8] (Figure 1). In these conditions PTX3-deficiency was associated with inCurrent Opinion in Immunology 2016, 38:39–44

42 Innate immunity

Figure 1

S-S e

f

g

S-S S-S

h S-S S-S C317-C318

S-S

Chr3q25 Ex 1 mRNA 1866 bp

C210-C271

Ex 3

Ex 2

Prot 381 aa SP NPD

PTX

S S

S S

myeloid DC

PMN

C179-C357

PTX3 C-terminal domain

PTX signature (HxCxS/TWxS)

S-S S-S S-S a

c

b

stromal cells

Mø

S-S S-S d

S-S

neutral/acidic pH

acidic pH (“switch on” signal)

Recognition of microbial moieties complement components FcγRs P-selectin

Binding to Fibrin and Plasminogen

Host defense and regulation of inflammation

Resolution/Orchestration of tissue repair Current Opinion in Immunology

An acidic pH sets the PTX3 molecule in a tissue repair mode.

creased clot formation, fibrin deposition and persistence, followed by increased collagen deposition. In vitro and in vivo studies demonstrated that by interacting through the N-terminal domain with fibrin and plasminogen at acidic conditions, which occur in damaged tissues, PTX3 promoted remodeling of the fibrin-rich inflammatory matrix ensuring a normal tissue repair, thus providing a novel link between innate immunity, haemostasis and tissue repair. The interaction of PTX3 with the provisional matrix component fibrinogen/fibrin and plasminogen was pH dependent, in that optimal binding was observed at acidic pH in vitro and in vivo. Thus, the acidic pH observed at sites of tissue damage and inflammation sets the PTX3 molecule in a tissue repair mode, without interfering with microbial recognition.

Concluding remarks PTX3 is evolutionarily well conserved in terms of expression, regulation and function. Gene targeted mice have allowed defining the functional roles of this molecule in innate immunity and inflammation and genetic and epigenetic data are consistent with the hypothesis that PTX3 exerts similar functions in humans. As a component of the humoral arm of innate immunity, PTX3 acts as functional Current Opinion in Immunology 2016, 38:39–44

predecessor of antibodies, by contributing to complement activation, opsonization of pathogens and glycosylationdependent regulation of inflammation. Recently PTX3 has emerged as an extrinsic oncosuppressor acting as key regulator of complement-driven, macrophage-mediated tumor promotion. Figure 2

Extracellular Matrix

Innate Immunity

Fibrinogen Mindin

Fibronectin

SAP

PTX3

Osteopontin

C1q

CRP

Vitronectin Collectins

Tissue remodelling and repair Antimicrobial resistance Current Opinion in Immunology

Matrix and microbe recognition as related functions. www.sciencedirect.com

PTX3 in innate immunity and inflammation Garlanda et al. 43

It has long been known but poorly appreciated that extracellular matrix components (e.g. fibronectin, mindin, osteopontin, vitronectin) (Figure 2) have opsonic activity [47,48]. On the other hand, modules of extracellular matrix proteins are essential constituents of humoral PRM, such as the fibrinogen domain in ficolins [2]. Moreover, humoral PRM interact with matrix components [49,50,51,52] as shown for PTX3 and fibrinogen/fibrin. The ancestral function of fibrinogen-like molecules was resistance rather than hemostasis. On this basis we propose that matrix and microbial recognition are related functions of PRM in an evolutionary perspective.

Conflict of interest AM, CG, BB are inventors of patents related to PTX3 and receive royalties on PTX3-related reagents.

Acknowledgments The financial support of the European Commission (ERC-PHII, FP7HEALTH-2011-ADITEC-N8280873), Ministero dell’Istruzione, dell’Universita` e della Ricerca (MIUR) (project FIRB RBAP11H2R9), the Italian Association for Cancer Research (AIRC) is gratefully acknowledged.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Garlanda C, Bottazzi B, Bastone A, Mantovani A: Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005, 23:337-366.

2.

Bottazzi B, Doni A, Garlanda C, Mantovani A: An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 2010, 28:157-183.

3.

Garlanda C, Hirsch E, Bozza S, Salustri A, De Acetis M, Nota R, Maccagno A, Riva F, Bottazzi B, Peri G et al.: Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 2002, 420:182-186.

4.

5.

Jeannin P, Bottazzi B, Sironi M, Doni A, Rusnati M, Presta M, Maina V, Magistrelli G, Haeuw JF, Hoeffel G et al.: Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors. Immunity 2005, 22:551-560. Jaillon S, Peri G, Delneste Y, Fremaux I, Doni A, Moalli F, Garlanda C, Romani L, Gascan H, Bellocchio S et al.: The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007, 204:793-804.

Jaillon S, Moalli F, Ragnarsdottir B, Bonavita E, Puthia M, Riva F, Barbati E, Nebuloni M, Cvetko Krajinovic L, Markotic A et al.: The Humoral Pattern Recognition Molecule PTX3 Is a Key Component of Innate Immunity against Urinary Tract Infection. Immunity 2014, 40:621-632. The study shows that PTX3 is an essential component of innate resistance against urinary tract infections and underlines that the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against this infection.

6. 

7. 

Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, Greco C, Feruglio F, Molgora M, Laface I et al.: PTX3 is an extrinsic oncosuppressor regulating complementdependent inflammation in cancer. Cell 2015, 160:700-714. The study shows that a component of the humoral arm of innate immunity, PTX3, acts as an extrinsic oncosuppressor gene in mouse and man by regulating complement-dependent, macrophage-sustained, tumorpromoting inflammation.

www.sciencedirect.com

Doni A, Musso T, Morone D, Bastone A, Zambelli V, Sironi M, Castagnoli C, Cambieri I, Stravalaci M, Pasqualini F et al.: An acidic microenvironment sets the humoral pattern recognition molecule PTX3 in a tissue repair mode. J Exp Med 2015, 212:905-925. The study shows that a prototypic component of humoral innate immunity, PTX3, plays a nonredundant role in the orchestration of tissue repair and remodeling by interacting with fibrin and plasminogen, and suggests that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity.

8. 

9.

Salio M, Chimenti S, De Angelis N, Molla F, Maina V, Nebuloni M, Pasqualini F, Latini R, Garlanda C, Mantovani A: Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation 2008, 117:1055-1064.

10. Inforzato A, Rivieccio V, Morreale AP, Bastone A, Salustri A, Scarchilli L, Verdoliva A, Vincenti S, Gallo G, Chiapparino C et al.: Structural characterization of PTX3 disulfide bond network and its multimeric status in cumulus matrix organization. J Biol Chem 2008, 283:10147-10161. 11. Inforzato A, Peri G, Doni A, Garlanda C, Mantovani A, Bastone A, Carpentieri A, Amoresano A, Pucci P, Roos A et al.: Structure and function of the long pentraxin PTX3 glycosidic moiety: finetuning of the interaction with C1q and complement activation. Biochemistry 2006, 45:11540-11551. 12. Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M, Valentino S et al.: Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 2010, 11:328-334. 13. Job ER, Bottazzi B, Short KR, Deng YM, Mantovani A, Brooks AG, Reading PC: A single amino acid substitution in the hemagglutinin of H3N2 subtype influenza A viruses is associated with resistance to the long pentraxin PTX3 and enhanced virulence in mice. J Immunol 2014, 192:271-281. 14. Jaillon S, Mancuso G, Hamon Y, Beauvillain C, Cotici V, Midiri A, Bottazzi B, Nebuloni M, Garlanda C, Fremaux I et al.: Prototypic long pentraxin PTX3 is present in breast milk, spreads in tissues, and protects neonate mice from Pseudomonas aeruginosa lung infection. J Immunol 2013, 191:1873-1882. 15. Bottazzi B, Santini L, Savino S, Giuliani MM, Duenas Diez AI, Mancuso G, Beninati C, Sironi M, Valentino S, Deban L et al.: Recognition of Neisseria meningitidis by the long pentraxin PTX3 and its role as an endogenous adjuvant. PLoS One 2015, 10:e0120807. 16. Foo SS, Chen W, Taylor A, Sheng KC, Yu X, Teng TS, Reading PC, Blanchard H, Garlanda C, Mantovani A et al.: Role of pentraxin 3 in shaping arthritogenic alphaviral disease: from enhanced viral replication to immunomodulation. PLoS Pathog 2015, 11:e1004649. 17. Foo SS, Reading PC, Jaillon S, Mantovani A, Mahalingam S: Pentraxins and collectins: friend or foe during pathogen invasion? Trends Microbiol 2015. (In press). 18. Olesen R, Wejse C, Velez DR, Bisseye C, Sodemann M, Aaby P, Rabna P, Worwui A, Chapman H, Diatta M et al.: DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans. Genes Immun 2007, 8:456-467. 19. Chiarini M, Sabelli C, Melotti P, Garlanda C, Savoldi G, Mazza C, Padoan R, Plebani A, Mantovani A, Notarangelo LD et al.: PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients. Genes Immun 2010, 11:665-670. 20. Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M,  Loffler J, Maertens JA, Bell AS, Inforzato A et al.: Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. New Engl J Med 2014, 370:421-432. This study shows that PTX3 SNPs modify the risk of invasive aspergillosis in patients undergoing hematopoietic stem-cell transplantation and that a specific donor haplotype was associated with reduced PTX3 in phagocytes that affected the antifungal capacity of neutrophils. 21. Wojtowicz A, Lecompte TD, Bibert S, Manuel O, Rueger S, Berger C, Boggian K, Cusini A, Garzoni C, Hirsch H et al.: PTX3 Current Opinion in Immunology 2016, 38:39–44

44 Innate immunity

polymorphisms and invasive mold infections after solid organ transplant. Clin Infect Dis 2015, 61:619-622. 22. Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d’Arienzo C, Fanelli R, Garlanda C et al.: Influence of pentraxin 3 (PTX3) genetic variants on myocardial infarction risk and PTX3 plasma levels. PLoS One 2012, 7:e53030. 23. Jaillon S, Bonavita E, Gentile S, Rubino M, Laface I, Garlanda C, Mantovani A: The long pentraxin PTX3 as a key component of humoral innate immunity and a candidate diagnostic for inflammatory diseases. Int Arch Allergy Immunol 2014, 165: 165-178. 24. Cotena A, Maina V, Sironi M, Bottazzi B, Jeannin P, Vecchi A, Corvaia N, Daha MR, Mantovani A, Garlanda C: Complement dependent amplification of the innate response to a cognate microbial ligand by the long pentraxin PTX3. J Immunol 2007, 179:6311-6317. 25. Dias AA, Goodman AR, Dos Santos JL, Gomes RN, Altmeyer A, Bozza PT, Horta MF, Vilcek J, Reis LF: TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis. J Leukoc Biol 2001, 69:928-936.

37. Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature 2008, 454:436-444. 38. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A: Cancerrelated inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009, 30:1073-1081. 39. Markiewski MM, DeAngelis RA, Benencia F, RicklinLichtsteiner SK, Koutoulaki A, Gerard C, Coukos G, Lambris JD: Modulation of the antitumor immune response by complement. Nat Immunol 2008, 9:1225-1235. 40. Ning C, Li YY, Wang Y, Han GC, Wang RX, Xiao H, Li XY, Hou CM,  Ma YF, Sheng DS et al.: Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1beta/IL-17A axis. Mucosal Immunol 2015. doi:10.1038/mi.2015.18 [Epub ahead of print]. This study shows that C5a is a potent inducer of IL-1b and IL-17 response in neutrophils thus promoting colon carcinogenesis in mice. 41. Wang JX, He YL, Zhu ST, Yang S, Zhang ST: Aberrant methylation of the 3q25 tumor suppressor gene PTX3 in human esophageal squamous cell carcinoma. World J Gastroenterol 2011, 17:4225-4230.

26. Doni A, Garlanda C, Bottazzi B, Meri S, Garred P, Mantovani A: Interactions of the humoral pattern recognition molecule PTX3 with the complement system. Immunobiology 2012, 217:1122-1128.

42. Presta M, Camozzi M, Salvatori G, Rusnati M: Role of the soluble pattern recognition receptor PTX3 in vascular biology. J Cell Mol Med 2007, 11:723-738.

27. Nauta AJ, Bottazzi B, Mantovani A, Salvatori G, Kishore U, Schwaeble WJ, Gingras AR, Tzima S, Vivanco F, Egido J et al.: Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol 2003, 33:465-473.

43. Ronca R, Alessi P, Coltrini D, Di Salle E, Giacomini A, Leali D, Corsini M, Belleri M, Tobia C, Garlanda C et al.: Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer. J Pathol 2013, 230:228-238.

28. Deban L, Jarva H, Lehtinen MJ, Bottazzi B, Bastone A, Doni A, Jokiranta TS, Mantovani A, Meri S: Binding of the long pentraxin PTX3 to factor H: interacting domains and function in the regulation of complement activation. J Immunol 2008, 181:8433-8440.

44. Ronca R, Giacomini A, Di Salle E, Coltrini D, Pagano K, Ragona L, Matarazzo S, Rezzola S, Maiolo D, Torrella R et al.: Longpentraxin 3 derivative as a small-molecule FGF trap for cancer therapy. Cancer Cell 2015, 28:225-239.

29. Ma YJ, Doni A, Hummelshoj T, Honore C, Bastone A, Mantovani A, Thielens NM, Garred P: Synergy between ficolin-2 and pentraxin 3 boosts innate immune recognition and complement deposition. J Biol Chem 2009, 284:28263-28275.

45. Chi JY, Hsiao YW, Li CF, Lo YC, Lin ZY, Hong JY, Liu YM, Han X, Wang SM, Chen BK et al.: Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drugresistant cancers. Oncotarget 2015, 6:23987-24001.

30. Ma YJ, Doni A, Romani L, Jurgensen HJ, Behrendt N, Mantovani A, Garred P: Ficolin-1-PTX3 complex formation promotes clearance of altered self-cells and modulates IL-8 production. J Immunol 2013, 191:1324-1333.

46. Chang WC, Wu SL, Huang WC, Hsu JY, Chan SH, Wang JM, Tsai JP, Chen BK: PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. Oncotarget 2015, 6: 7741-7757.

31. Ma YJ, Doni A, Skjoedt MO, Honore C, Arendrup M, Mantovani A, Garred P: Heterocomplexes of mannose-binding lectin and the pentraxins PTX3 or serum amyloid P component trigger crossactivation of the complement system. J Biol Chem 2011, 286:3405-3417.

47. Proctor RA: Fibronectin: an enhancer of phagocyte function. Rev Infect Dis 1987, 9(Suppl 4):S412-S419.

32. Braunschweig A, Jozsi M: Human pentraxin 3 binds to the  complement regulator c4b-binding protein. PLoS One 2011, 6:e23991. This study shows that in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP, thus preventing excessive local complement activation and host tissue damage. 33. Csincsi AI, Kopp A, Zoldi M, Banlaki Z, Uzonyi B, Hebecker M, Caesar JJ, Pickering MC, Daigo K, Hamakubo T et al.: Factor Hrelated protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation. J Immunol 2015, 194:4963-4973. 34. Gout E, Moriscot C, Doni A, Dumestre-Perard C, Lacroix M, Perard J, Schoehn G, Mantovani A, Arlaud GJ, Thielens NM: Mficolin interacts with the long pentraxin PTX3: a novel case of cross-talk between soluble pattern-recognition molecules. J Immunol 2011, 186:5815-5822. 35. Kopp A, Strobel S, Tortajada A, Rodriguez de Cordoba S, Sanchez-Corral P, Prohaszka Z, Lopez-Trascasa M, Jozsi M: Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor h and factor h-related protein 1 to pentraxin 3. J Immunol 2012, 189:1858-1867. 36. Lech M, Rommele C, Grobmayr R, Eka Susanti H, Kulkarni OP, Wang S, Grone HJ, Uhl B, Reichel C, Krombach F et al.: Endogenous and exogenous pentraxin-3 limits postischemic acute and chronic kidney injury. Kidney Int 2013, 83:647-661. Current Opinion in Immunology 2016, 38:39–44

48. He YW, Li H, Zhang J, Hsu CL, Lin E, Zhang N, Guo J, Forbush KA,  Bevan MJ: The extracellular matrix protein mindin is a patternrecognition molecule for microbial pathogens. Nat Immunol 2004, 5:88-97. This study shows that mindin binds to bacteria functioning as an opsonin for macrophage phagocytosis. This paper provides compelling evidence that ECM components can also serve as an integral part of the innate immunity. 49. Groeneveld TW, Oroszlan M, Owens RT, Faber-Krol MC, Bakker AC, Arlaud GJ, McQuillan DJ, Kishore U, Daha MR, Roos A: Interactions of the extracellular matrix proteoglycans decorin and biglycan with C1q and collectins. J Immunol 2005, 175:4715-4723. 50. Dyck RF, Lockwood CM, Kershaw M, McHugh N, Duance VC, Baltz ML, Pepys MB: Amyloid P-component is a constituent of normal human glomerular basement membrane. J Exp Med 1980, 152:1162-1174. 51. Suresh MV, Singh SK, Agrawal A: Interaction of calcium-bound C-reactive protein with fibronectin is controlled by pH: in vivo implications. J Biol Chem 2004, 279:52552-52557. 52. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T,  Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD et al.: Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med 2015, 373:1106-1114. This paper provides compelling evidence that treatments targeting SAP safely trigger the rapid clearance of amyloid deposits from the liver and other tissues. www.sciencedirect.com